Programmed cell death plays a central role in development and in many diseases. The long term goal of our research is to understand the mechanisms of programmed cell death in the Drosophila ovary, a model system with unique advantages in genetics and cell biology. The cell death genes identified thus far in Drosophila are generally homologous to the genes controlling cell death in mammals. The vast majority of cells that undergo cell death in Drosophila use a common pathway that is increasingly well-understood. However, cell death in the ovary occurs by distinct genetic pathways. This proposal aims to uncover the mechanisms controlling two types of cell death that occur in the fly ovary: developmental cell death of nurse cells, and stress-induced death of entire follicles. Stress-induced cell death requires caspases, whereas caspases are only partially required for developmental nurse cell death. Recent findings indicate that autophagy and mitochondrial morphological changes are occurring during both forms of cell death. The proposal aims to uncover the contribution of autophagy and mitochondria to cell death in the ovary. Additionally a genetic screen will be carried out to identify genes that function in ovarian cell death, perhaps in a pathway that acts in parallel to the caspases. Nutrition and the insulin signaling pathway are known to control egg chamber progression through oogenesis. Components of the insulin signaling pathway will be investigated for their effects on both autophagy and apoptosis in the ovary. Given the high conservation of cell death mechanisms between Drosophila and mammals identified thus far, we expect that pathways that we uncover in the fly ovary will be conserved in humans. A complete understanding of the diverse mechanisms controlling cell death may reveal new therapeutic targets for diseases with excessive or insufficient cell death such as neurodegenerative disorders and cancer. Public Health Relevance: Programmed cell death plays a central role in development and in many diseases. The long term goal of our research is to understand the mechanisms of programmed cell death in the Drosophila ovary, a model system with unique advantages in genetics and cell biology. A complete understanding of the diverse mechanisms controlling cell death may reveal new therapeutic targets for diseases with excessive or insufficient cell death such as neurodegenerative disorders and cancer.